Public Release: 24-Feb-2014
JCI early table of contents for Feb. 24, 2014

Pulmonary emphysema results in irreversible lung damage and is most often the result of long term cigarette smoke exposure. Immune cells, such as macrophages and myeloid dendritic cells (mDCs) accumulate in the lungs of smokers with emphysema and release cytokines associated with autoimmune and inflammatory responses. In this issue of the Journal of Clinical Investigation Farrah Kheradmand and colleagues at Baylor University found that peroxisome proliferator activated receptor-γ (PPARγ) is downregulated in mDCs isolated from the lungs of emphysema patients and mice exposed to chronic cigarette smoke. Mice with PPARγ-deficient mDCs exhibited spontaneous lung inflammation and emphysema; moreover, treatment of smoke-exposed mice with a PPARγ agonist reversed emphysema development despite continuous exposure to cigarette smoke. In the accompanying commentary, Neil Kelly and Steven Shapiro of the University of Pennsylvania discuss the potential of PPARγ agonists to restore lung capacity in emphysema patients.

Dysfunctional regulation of the excitatory neurotransmitter glutamate can lead to excitotoxicity and neurodegeneration. The excitatory amino acid transporter 2 (EAAT2), which is responsible for glutamate uptake is frequently reduced in patients with neurodegenerative diseases such as Alzheimer's disease and ALS. In this issue of the Journal of Clinical Investigation, Chien-Liang Glenn Lin and colleagues at the Ohio State University used a murine model of ALS to examine the ability of a drug compound (LDN/OSU-0212320) to enhance expression of EAAT2 and reduce levels of synaptic glutamate. They found that this compound increased EAAT2 expression and protected cultured neurons from exocitotoxic injury and death. Furthermore, LDN/OSU-0212320 treatment delayed the onset of neurodegenerative-associated declines in motor function and extended lifespan ALS mice. In the accompanying commentary, Allison Limpert and Nicholas Cosford of the Sanford Burnham Institute for Medical Research discus the potential benefits of EEAT2 modulation in treating neurodegenerative disease.

BRAF inhibitors (BRAFi) are a first line treatment for BRAFV600E mutant melanoma; however, despite initial positive responses to treatment, nearly all patients develop BRAFi resistance. In this issue of the Journal of Clinical Investigation, Ravi Amaravadi and colleagues at the University of Pennsylvania found that BRAFi-resistant tumors exhibit higher levels of autophagy compared to baseline tumors and that the level of therapy-induced autophagy correlated with lower response rates and shorter progression-free survival times. The authors demonstrated that BRAFi therapy-associated autophagy is mediated by GRP78-dependent induction of ER stress. A combination of BRAF and autophagy inhibition promoted tumor regression in a murine xenograft model of BRAFi-resistant melanoma. In an accompanying Commentary, Shirish Shenolikar of Duke-NUS discusses how further work should be done to evaluate the combined use of BRAFi and autophagy inhibitors for melanoma treatment.

X-linked centronuclear myopathy (XLCNM) is a muscle wasting disease with early onset and poor prognosis. XLCNM results from myotubularin (MTM1) loss-of-function mutations, while autosomal CNM can result from dynamin 2 (DNM2) dominant mutations. In this issue of the Journal of Clinical Investigation, Belinda Cowling and colleagues found that DNM2 levels were elevated in XLCNM patients and in a murine model of XLCNM. T Deletion of one copy of Dnm2 in Mtm1 mutant mice increased lifespan, whole body strength, and diaphragm function to levels similar to control animals. Additionally, muscle strength was increased and histological features were ameliorated or delayed. In the accompanying commentary, Alexis Demonbreun and Elizabeth McNally of the University of Chicago discuss the cellular mechanisms underlying DNM2s effects in XLCNM.

Rejection of grafted organs, especially lungs, is a major obstacle for transplantation therapy. Memory CD8+ T cell responses are believed to play a critical role in the rejection of transplanted organs and new pre-clinical protocols that specifically target memory T cell populations are currently in development. In this issue of the Journal of Clinical Investigation, Daniel Kreisel and colleagues at Washington University demonstrated that lung allograft acceptance in a murine lung allograft model is actually dependent on graft infiltration by central memory CD8+ T cells. Using two-photon intravital microscopy, Krupnick and colleagues found that T cell expression of the chemokine CCR7 was required for stable interactions with antigen presenting cells in murine lung allograft recipients. The interactions between T cells and antigen-presenting cells resulted in IFNγ and NO production, and subsequent dampening of the immune response. In an accompanying Commentary, Xinguo Jiang and Mark R. Nicolls of Stanford University discuss how these findings impact our understanding of the mechanisms underlying lung allograft acceptance.

The central nervous system (CNS) is an immune privileged site; however, the mechanisms that confer this privilege are poorly understood. Failure of the CNS to maintain an anti-inflammatory state results in multiple sclerosis (MS) and other disease states. In this issue of the Journal of Clinical Investigation, David Brown and colleagues at the University of New South Wales identified a pathway for CNS immune cell traffic that is associated with the rostral migratory stream (RMS), a neuronal stem cell pathway that originates in the subventricular zone (SVZ) and extends to the olfactory bulb. From here, dendritic cells (DCs) migrate to the cervical lymph nodes where a subset increases T-regulatory cell activity, reducing anti-CNS autoimmune responses in mice. Importantly, disrupting this pathway leads to retention of DCs in the brain and increases cervical lymph node anti-CNS autoimmune responses. As a consequence CNS immune tolerance is broken resulting in spontaneous experimental autoimmune encephalitits and associated neuronal destruction. In the accompanying commentary, Gianvito Martino and colleagues at the San Raffaele Scientific Institute discuss the role of the SVZ in neuroprotection.

Heart damage associated with myocardial infarction (MI) instigates an immune-mediated wound healing response that clears debris and restores tissue integrity, but also leads to fibrotic scarring, pathological remodeling, and a decline in cardiac function. In contrast, damaged neonatal mouse heart can regenerate without scarring, but this capacity is lost by postnatal day 7 (P7). In this issue of the Journal of Clinical Investigation, Eric Olson and colleagues at the University of Texas Southwestern Medical Center compared the immune response to heart damage in mice at P1 and P14 and found that heart regeneration following MI is dependent on a neonatal macrophage response. Further characterization of these cells revealed that regenerative macrophages secrete soluble factors that may play a role in regeneration. In the accompanying commentary, Paul Riley proposes that a better understanding of the immune modulators that promote regeneration could potentially be exploited to induce regeneration in adult heart.

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